Dysregulation of System Xc- and Its Impact on Cocaine Seeking

Abnormal glutamate signaling in the brain, particularly in the nucleus accumbens core, contributes to compulsive cocaine-seeking behavior. In the nucleus accumbens, two distinct pools of glutamate exist. The synaptic pool stimulates excitatory postsynaptic receptors, leading to cocaine seeking. Cystine-glutamate exchange by system xc- contributes to the extrasynaptic pool and regulates neurotransmission by activating extrasynaptic receptors including inhibitory Group II metabotropic glutamate receptors, positioning this as an important mechanism for regulating nucleus accumbens activity. We and others have found decreased levels of cystine-glutamate exchange in animals withdrawn from chronic cocaine administration. In chapter 1, we describe studies directly implicating diminished system xc- activity in abnormal glutamate signaling necessary for promoting drug seeking. Given that altered system xc- activity is essential to drug seeking, understanding the cellular basis of reduced cystine-glutamate exchange would advance our knowledge of the neural basis of addiction. Unfortunately, little is known about how the system is regulated. To address this, we sought to define conditions that permit the study of system xc- (chapter 2). In chapter 3, we examined potential regulation of xc- by dopamine, nonspecific dopamine agonists, D1-liked dopamine receptor agonists, and D2-like dopamine receptor agonists. While we found D1-like receptor regulation of cystine-glutamate exchange in mixed cortical culture, we did not observe this effect in tissue punches; thus, it is unlikely that abnormal regulation of system xc- by dopamine underlies reduced cystine-glutamate exchange in cocaine-withdrawn animals. In chapter 4, we examined pituitary adenylyl cyclase activating polypeptide (PACAP) because it has been recently shown to regulate extracellular glutamate homeostasis. We found acute and tonic regulation of cystine-glutamate exchange by PACAP-induced stimulation of Ca2+-dependent protein kinase (PKC) activity. More importantly, we also determined that PACAP regulation of system xc- is diminished in animals withdrawn from cocaine self-administration. These findings suggest dysregulated PACAP neurotransmission in cocaine-withdrawn animals contributes to the neural basis of addiction. By revealing novel mechanisms contributing to addiction, scientists can identify novel targets for therapeutic treatment